Circular RNAs (circRNAs), which belong to the category of non-coding RNAs, play an important role in the development and spread of cancer. They are thought to function primarily as sponges for microRNAs or as platforms that facilitate interactions with protein complexes, yet their complete spectrum of biological roles is still not fully understood. In recent studies, certain circRNAs have been discovered to possess the ability to encode proteins. To determine the involvement of circular RNAs in gastric cancer (GC), high-throughput sequencing was conducted on five matched pairs of tumor and adjacent normal tissues. This analysis identified circAXIN1 as a significantly dysregulated circRNA with the potential to produce a previously unknown protein. The translational capability of circAXIN1 was verified by generating FLAG-labeled circRNA expression constructs and performing Western blotting, mass spectrometry, and dual-luciferase reporter assays. Functional gain- and loss-of-expression approaches were subsequently employed to assess the effects of circAXIN1 and its translated product, AXIN1-295aa, on GC cell growth, motility, invasiveness, and metastatic capacity in both cellular and animal models. The competitive binding relationship between AXIN1-295aa and adenomatous polyposis coli (APC) was analyzed using co-immunoprecipitation techniques. Activation of the Wnt pathway was evaluated through Top/Fopflash reporter assays in combination with quantitative RT-PCR, Western blot analysis, immunofluorescence microscopy, and chromatin immunoprecipitation assays.CircAXIN1 is markedly upregulated in gastric cancer (GC) tissues relative to matched adjacent noncancerous gastric samples. It was found to translate a previously unrecognized 295–amino acid protein, designated AXIN1-295aa. Ectopic expression of circAXIN1 significantly promotes GC cell proliferation, migration, and invasiveness, whereas silencing circAXIN1 suppresses these malignant phenotypes both in vitro and in vivo. Mechanistically, AXIN1-295aa competes with adenomatous polyposis coli (APC) for binding, thereby impairing the integrity of the Wnt signaling destruction complex. As a result, stabilized β-catenin accumulates and translocates into the nucleus, where it associates with TCF binding elements in target gene promoters to activate downstream transcriptional programs. CircAXIN1 was shown to produce a newly characterized protein, AXIN1-295aa, which exerts tumor-promoting effects by stimulating Wnt pathway activity. Through this mechanism, AXIN1-295aa contributes to the development and advancement of gastric cancer, indicating its promise as a novel molecular target for therapeutic intervention.
